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Published on: May 6, 2014
Sustained inflammation due to nuclear factor-kappa B activation in irradiated human arteries
Martin Halle1, Anders Gabrielsen2, Gabrielle Paulsson-Berne3
1Department of Molecular Medicine and Surgery, Section of Reconstructive Plastic Surgery, Karolinska Institute, Stockholm, Sweden; Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
Objectives:
The aim of this study was to investigate gene expression networks related to cardiovascular disease in radiated human arteries.
Background:
Recent epidemiological studies have shown that radiotherapy is associated with cardiovascular disease years after treatment. However, the molecular mechanisms underlying late effects of radiation are poorly described.
Methods:
Arterial biopsies from radiated and nonradiated human conduit arteries, from the same patient, were simultaneously harvested during microvascular free tissue transfer for cancer-reconstruction in 13 patients, 4 to 500 weeks from radiation treatment. Radiated and nonradiated arteries were compared, with Affymetrix (Santa Clara, California) microarrays on a subset of the material to generate candidate genes. A Taqman (Applied Biosystems, Foster City, California) low-density array of 45 selected genes was designed for analysis of the whole material.
Results:
Thirteen genes were synchronously expressed in all patients (p = 0.0015), including CCL8, CCL3, CXCL2, DUSP5, FGFR2, HMOX1, HOXA9, IL-6, MMP-1, PTX3, RDH10, SOD2, and TNFAIP3. A majority of differentially regulated genes related to the nuclear factor-kappa B (NF-kappaB) signaling pathway and were dysregulated even years after radiation. The NF-kappaB activation was confirmed by immunohistochemistry and immunofluorescence.
Conclusions:
In the present study, we found sustained inflammation due to NF-kappaB activation in human radiated arteries. The results are supported by previous in vitro findings suggesting that deoxyribonucleic acid injury, after radiation, activates NF-kappaB. We also suggest that HOXA9 might be involved in the regulation of NF-kappaB activation. The observed sustained inflammatory response can explain cardiovascular disease years after radiation.
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